PROJECT SUMMARY The Genotype Tissue Expression (GTEx) Consortium has identified thousands of expression quantitative trait loci (eQTLs) in the human population that affect gene expression in multiple tissues. These regulatory variants are enriched in cis-regulatory elements and co-localize with GWAS loci, implying that many eQTLs act via non-coding mechanisms to impact human phenotype and possibly cause disease. Current research efforts suggest that noncoding eQTLs? effects on gene expression are primarily mediated by altered transcription factor (TF) binding affinity. Long-term objective: Given the biological relevance of tissue in disease phenotypes and the impact of environmental effects on cell state on disease penetrance, understanding the context variability of eQTLs is crucial for unraveling their genetic contributions to complex traits and disease. Central hypothesis: Since TF activity levels vary among cell types and between individuals, I hypothesize that the observed context variability of many eQTLs is explained by varying TF levels. Research design and methods: I propose to use the natural variation of TF activity among tissues and between individuals to elucidate mechanisms of action of eQTL regulatory variants and understand context specificity of eQTL effects. I will then exploit these mechanisms to understand tissue variability and gene-by-environment interactions of GWAS effects. To do so, I will use data from the GTEx Consortium v8 release, which includes 838 individuals? whole genome sequences and their RNA- seq data from a total of 15,201 samples across 49 tissues. Specific aims: In Aim 1, I will characterize tissue- variable mechanisms of eQTLs and their application to human disease, which will discover upstream trans-acting regulators of a subset of eQTLs and will propose causal mechanisms and trans-regulators of GWAS loci. Aim 2 focuses on eQTL differences between individuals and environmental modifiers of eQTL effects, and I will use these analyses to identify gene-by-environment interactions of common diseases and complex traits. My proposed research will elucidate mechanisms of actions and trans-regulators of specific eQTLs and GWAS loci, and it will discover gene-by-environment interactions that affect disease penetrance. It promises a deeper understanding of gene regulation and of genetic and environmental contributions to complex traits and disease. Fellowship training plan: My proposed research training plan allows me to capitalize on my strengths and previous experiences, and it will improve my skills in statistics and computational genomic data analysis, as well as in study design, critical thinking, communication, mentorship, leadership, and professional development. Environment: During my training plan, I am able to benefit from multiple research communities, including my sponsor?s (Dr. Tuuli Lappalainen), lab, my cosponsor?s (Dr. Harmen Bussemaker) lab, the New York Genome Center, the Columbia Integrated PhD Program, and the Columbia Department of Systems Biology.